Dopamine receptors have been divided into two general categories, designated D-1 and D-2 receptors in the central nervous system (CNS). This division is made on the basis of pharmacological an biochemical differences between the two types of receptors. The D-1 receptor is linked to the enzyme adenylate cyclase so that stimulation of this receptor increases cyclic adenosine 3',5' monophosphate (cAMP) production. The D-2 receptor also regulates important functional activity within the CNS. The autoreceptors on dopaminergic neurons control the firing rate of these neuronal cells as well as the release of dopamine from the terminals of these neuronal cells. This autoreceptor has the pharmacological properties of a D-2 receptor. Likewise, the D-2 receptors on the cholinergic interneurons in the striatum regulate the release of acetylcholine from these cells. Finally, tonic stimulation of the D-2 receptors on the mammotrophs of the anterior pituitary suppresses prolactin secretion.
Dopamine occurs at high concentrations within the nerve terminals in the basal ganglia of the mammalian brain. In the early 1960's, the loss of striatal dopamine was established as a chemical sign of Parkinson's Disease. This deficiency is still thought to be primary to the etiology of the disease state.
L-DOPA (dihydroxyphenylalanine), when used in conjunction with a peripheral aromatic amino acid decarboxylase inhibitor, and often supplemented with anticholinergic agents, has been shown to be useful in the treatment of Parkinson's Disease. It is theorized that the therapeutic response to L-DOPA is a result of the conversion of L-DOPA into dopamine within the striatum, and thus the response is linked to stimulation of both the D-1 and D-2 receptors.
The success of L-DOPA therapy has led to the testing of other compounds capable of mimicking the post synaptic receptor actions of dopamine. Such direct acting agents might offer the therapeutic advantages of greater potency, increased duration of action, or fewer side effects over L-DOPA.
For example, bromocriptine, the direct acting dopamine agonist most widely used in the treatment of Parkinson's Disease, lowers the amount of L-DOPA required to achieve the maximal therapeutic response and allows for a delay in the onset of L DOPA therapy. However, the response to bromocriptine alone is not as great as that of L-DOPA.
Dopaminergic agents that show selectivity for different receptor subtypes are desirable in an effort to obtain the anticipated physiological response separate from other possibly less desirable effects.
Dopamine has been used in the treatment of shock, congestive heart failure, and renal failure. Stimulation of the peripheral DA-1 receptors causes vasodilation, particularly in the renal and mesenteric vascular beds where large numbers of these receptors are found. Dopamine's utility however has been limited by its ability to cause vasoconstriction at higher concentrations, presumably due to its secondary effects on adrenergic receptors, and by its emetic effects due to DA 2 stimulation. Agents selective for the peripheral DA-1 receptors may offer significant advantages over currently used treatments for these and other disorders.